tbuckley/cabot-search huggingface dataset:
Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results
Authors: Michael J. Mauro, Timothy P. Hughes, Dong-Wook Kim, Delphine Rea, Jorge E. Cortes, Andreas Hochhaus, Koji Sasaki, Massimo Breccia, Moshe Talpaz, Oliver Ottmann, Hironobu Minami, Yeow Tee Goh, Daniel J. DeAngelo, Michael C. Heinrich, Valle Gómez-García de Soria, Philipp le Coutre, Francois-Xavier Mahon, Jeroen J. W. M. Janssen, Michael Deininger, Naranie Shanmuganathan, Mark B. Geyer, Silvia Cacciatore, Fotis Polydoros, Nithya Agrawal, Matthias Hoch, Fabian Lang
Journal: Leukemia (2023)

Abstract Asciminib is approved for patients with Philadelphia chromosome–positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10–200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.
Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures
Authors: Tobias Rausch, Rene Snajder, Adrien Leger, Milena Simovic, Mădălina Giurgiu, Laura Villacorta, Anton G. Henssen, Stefan Fröhling, Oliver Stegle, Ewan Birney, Marc Jan Bonder, Aurelie Ernst, Jan O. Korbel
Journal: Cell Genomics (2023)

Cancer genomes harbor a broad spectrum of structural variants (SVs) driving tumorigenesis, a relevant subset of which escape discovery using short-read sequencing. We employed Oxford Nanopore Technologies (ONT) long-read sequencing in a paired diagnostic and post-therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assembled complex rearrangements, including a 1.55-Mbp chromothripsis event, and we uncover a complex SV pattern termed templated insertion (TI) thread, characterized by short (mostly <1 kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50 kbp in size. TI threads occur in 3% of cancers, with a prevalence up to 74% in liposarcoma, and frequent colocalization with chromothripsis. We also perform long-read-based methylome profiling and discover allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in cancer-driver genes. Our study shows the advantage of long-read sequencing in the discovery and characterization of complex somatic rearrangements.
Generalizable biomarker prediction from cancer pathology slides with self-supervised deep learning: A retrospective multi-centric study
Authors: Jan Moritz Niehues, Philip Quirke, Nicholas P. West, Heike I. Grabsch, Marko van Treeck, Yoni Schirris, Gregory P. Veldhuizen, Gordon G.A. Hutchins, Susan D. Richman, Sebastian Foersch, Titus J. Brinker, Junya Fukuoka, Andrey Bychkov, Wataru Uegami, Daniel Truhn, Hermann Brenner, Alexander Brobeil, Michael Hoffmeister, Jakob Nikolas Kather
Journal: Cell Reports Medicine (2023)

Deep learning (DL) can predict microsatellite instability (MSI) from routine histopathology slides of colorectal cancer (CRC). However, it is unclear whether DL can also predict other biomarkers with high performance and whether DL predictions generalize to external patient populations. Here, we acquire CRC tissue samples from two large multi-centric studies. We systematically compare six different state-of-the-art DL architectures to predict biomarkers from pathology slides, including MSI and mutations in BRAF, KRAS, NRAS, and PIK3CA. Using a large external validation cohort to provide a realistic evaluation setting, we show that models using self-supervised, attention-based multiple-instance learning consistently outperform previous approaches while offering explainable visualizations of the indicative regions and morphologies. While the prediction of MSI and BRAF mutations reaches a clinical-grade performance, mutation prediction of PIK3CA, KRAS, and NRAS was clinically insufficient.
Cryptosporidium uses multiple distinct secretory organelles to interact with and modify its host cell
Authors: Amandine Guérin, Katherine M. Strelau, Konstantin Barylyuk, Bethan A. Wallbank, Laurence Berry, Oliver M. Crook, Kathryn S. Lilley, Ross F. Waller, Boris Striepen
Journal: Cell Host & Microbe (2023)
Habitual daily intake of a sweet and fatty snack modulates reward processing in humans
Authors: Sharmili Edwin Thanarajah, Alexandra G. DiFeliceantonio, Kerstin Albus, Bojana Kuzmanovic, Lionel Rigoux, Sandra Iglesias, Ruth Hanßen, Marc Schlamann, Oliver A. Cornely, Jens C. Brüning, Marc Tittgemeyer, Dana M. Small
Journal: Cell Metabolism (2023)

Western diets rich in fat and sugar promote excess calorie intake and weight gain; however, the underlying mechanisms are unclear. Despite a well-documented association between obesity and altered brain dopamine function, it remains elusive whether these alterations are (1) pre-existing, increasing the individual susceptibility to weight gain, (2) secondary to obesity, or (3) directly attributable to repeated exposure to western diet. To close this gap, we performed a randomized, controlled study (NCT05574660) with normal-weight participants exposed to a high-fat/high-sugar snack or a low-fat/low-sugar snack for 8 weeks in addition to their regular diet. The high-fat/high-sugar intervention decreased the preference for low-fat food while increasing brain response to food and associative learning independent of food cues or reward. These alterations were independent of changes in body weight and metabolic parameters, indicating a direct effect of high-fat, high-sugar foods on neurobehavioral adaptations that may increase the risk for overeating and weight gain.
A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans
Authors: Anoma Nellore, Esther Zumaquero, Christopher D. Scharer, Christopher F. Fucile, Christopher M. Tipton, R. Glenn King, Tian Mi, Betty Mousseau, John E. Bradley, Fen Zhou, Stuti Mutneja, Paul A. Goepfert, Jeremy M. Boss, Troy D. Randall, Ignacio Sanz, Alexander F. Rosenberg, Frances E. Lund
Journal: Immunity (2023)
Adolescent PCOS: a postpubertal central obesity syndrome
Authors: Lourdes Ibáñez, Francis de Zegher
Journal: Trends in Molecular Medicine (2023)

Adolescent polycystic ovary syndrome (PCOS) is a highly prevalent, reversible, endocrine-metabolic mode essentially driven by ectopic fat, which, in turn, often results from a mismatch between early adipogenesis and later lipogenesis, or between prenatal and postnatal weight gain. The key features of adolescent PCOS are menstrual irregularity and androgen excess (hirsutism, acne, and/or high testosterone). Adolescent PCOS is frequently preceded by rapid maturation (early variants of adrenarche/pubarche and puberty/menarche, also accelerated by ectopic fat) and is diagnosed between 2 and 8 years after menarche, thus during late adolescence or early adulthood. Treatment of adolescent PCOS should not only focus on symptoms, but also reduce the amount of ectopic fat, thereby aiming for an overall state of preconception health.
Translocation t(6;7) in AML-M4 cell line GDM-1 results in MNX1 activation through enhancer-hijacking
Authors: Dieter Weichenhan, Anna Riedel, Charlotte Meinen, Alisa Basic, Reka Toth, Marion Bähr, Pavlo Lutsik, Joschka Hey, Etienne Sollier, Umut H. Toprak, Simge Kelekçi, Yu-Yu Lin, Mariam Hakobyan, Aurore Touzart, Ashish Goyal, Justyna A. Wierzbinska, Matthias Schlesner, Frank Westermann, Daniel B. Lipka, Christoph Plass
Journal: Leukemia (2023)
Correction to: Impact of pre-transplant induction and consolidation cycles on AML allogeneic transplant outcomes: a CIBMTR analysis in 3113AML patients
Authors: Michael Boyiadzis, Mei-Jie Zhang, Karen Chen, Hisham Abdel-Azim, Muhammad Bilal Abid, Mahmoud Aljurf, Ulrike Bacher, Talha Badar, Sherif M. Badawy, Minoo Battiwalla, Nelli Bejanyan, Vijaya Raj Bhatt, Valerie I. Brown, Paul Castillo, Jan Cerny, Edward A. Copelan, Charles Craddock, Bhagirathbhai Dholaria, Miguel Angel Diaz Perez, Christen L. Ebens, Robert Peter Gale, Siddhartha Ganguly, Lohith Gowda, Michael R. Grunwald, Shahrukh Hashmi, Gerhard C. Hildebrandt, Madiha Iqbal, Omer Jamy, Mohamed A. Kharfan-Dabaja, Nandita Khera, Hillard M. Lazarus, Richard Lin, Dipenkumar Modi, Sunita Nathan, Taiga Nishihori, Sagar S. Patel, Attaphol Pawarode, Wael Saber, Akshay Sharma, Melhem Solh, John L. Wagner, Trent Wang, Kirsten M. Williams, Lena E. Winestone, Baldeep Wirk, Amer Zeidan, Christopher S. Hourigan, Mark Litzow, Partow Kebriaei, Marcos de Lima, Kristin Page, Daniel J. Weisdorf
Journal: Leukemia (2023)
Evidence for the role of transcription factors in the co-transcriptional regulation of intron retention
Authors: Fahad Ullah, Saira Jabeen, Maayan Salton, Anireddy S. N. Reddy, Asa Ben-Hur
Journal: Genome biology (2023)

Alternative splicing is a widespread regulatory phenomenon that enables a single gene to produce multiple transcripts. Among the different types of alternative splicing, intron retention is one of the least explored despite its high prevalence in both plants and animals. The recent discovery that the majority of splicing is co-transcriptional has led to the finding that chromatin state affects alternative splicing. Therefore, it is plausible that transcription factors can regulate splicing outcomes.We provide evidence for the hypothesis that transcription factors are involved in the regulation of intron retention by studying regions of open chromatin in retained and excised introns. Using deep learning models designed to distinguish between regions of open chromatin in retained introns and non-retained introns, we identified motifs enriched in IR events with significant hits to known human transcription factors. Our model predicts that the majority of transcription factors that affect intron retention come from the zinc finger family. We demonstrate the validity of these predictions using ChIP-seq data for multiple zinc finger transcription factors and find strong over-representation for their peaks in intron retention events.This work opens up opportunities for further studies that elucidate the mechanisms by which transcription factors affect intron retention and other forms of splicing.Source code available at https://github.com/fahadahaf/chromir.
Histone Deacetylase 6 Inhibition Exploits Selective Metabolic Vulnerabilities in LKB1 Mutant, KRAS Driven NSCLC
Authors: Hua Zhang, Christopher S. Nabel, Dezhi Li, Ruth Í. O’Connor, Caroline R. Crosby, Sarah M. Chang, Yuan Hao, Robyn Stanley, Soumyadip Sahu, Daniel S. Levin, Ting Chen, Sittinon Tang, Hsin-Yi Huang, Mary Meynardie, Janaye Stephens, Fiona Sherman, Alison Chafitz, Naoise Costelloe, Daniel A. Rodrigues, Hilda Fogarty, Miranda G. Kiernan, Fiona Cronin, Eleni Papadopoulos, Magdalena Ploszaj, Vajira Weerasekara, Jiehui Deng, Patrick Kiely, Nabeel Bardeesy, Matthew G. Vander Heiden, Triona Ni Chonghaile, Catríona M. Dowling, Kwok-Kin Wong
Journal: Journal of Thoracic Oncology (2023)

IntroductionIn KRAS-mutant NSCLC, co-occurring alterations in LKB1 confer a negative prognosis compared with other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetic inhibition of histone deacetylase 6 (HDAC6) revealed the impaired activity of numerous enzymes involved in glycolysis. On the basis of these previous findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors.MethodsUsing cell lines derived from mouse autochthonous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo.ResultsSurprisingly, KL-mutant cells revealed reduced levels of redox-sensitive cofactors at baseline. This is associated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and antitumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo.ConclusionsExploring the differential metabolism of KL and KRAS/TP53-mutant NSCLC, we identified decreased metabolic reserve in KL-mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC on the basis of a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for the treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.
Clinical perspective: Antibody-drug conjugates for the treatment of HER2-positive breast cancer
Authors: Zohreh Najminejad, Fatemeh Dehghani, Yousef Mirzaei, Ali Hussein Mer, Seyyed Amirreza Saghi, Mohadeseh Haji Abdolvahab, Nader Bagheri, Anna Meyfour, Ameneh Jafari, Saeed Jahandideh, Tohid Gharibi, Zahra Amirkhani, Hamed Delam, Noushin Mashatan, Hosein Shahsavarani, Meghdad Abdollahpour-Alitappeh
Journal: Molecular Therapy (2023)

Antibody-drug conjugates (ADCs) are a promising class of cancer biopharmaceuticals that exploit the specificity of a monoclonal antibody (mAb) to selectively deliver highly cytotoxic small molecules to targeted cancer cells, leading to an enhanced therapeutic index through increased antitumor activity and decreased off-target toxicity. ADCs hold great promise for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer after the approval and tremendous success of trastuzumab emtansine and trastuzumab deruxtecan, representing a turning point in both HER2-positive breast cancer treatment and ADC technology. Additionally and importantly, a total of 29 ADC candidates are now being investigated in different stages of clinical development for the treatment of HER2-positive breast cancer. The purpose of this review is to provide an insight into the ADC field in cancer treatment and present a comprehensive overview of ADCs approved or under clinical investigation for the treatment of HER2-positive breast cancer. Antibody-drug conjugates (ADCs) are a promising class of cancer biopharmaceuticals that exploit the specificity of a monoclonal antibody (mAb) to selectively deliver highly cytotoxic small molecules to targeted cancer cells, leading to an enhanced therapeutic index through increased antitumor activity and decreased off-target toxicity. ADCs hold great promise for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer after the approval and tremendous success of trastuzumab emtansine and trastuzumab deruxtecan, representing a turning point in both HER2-positive breast cancer treatment and ADC technology. Additionally and importantly, a total of 29 ADC candidates are now being investigated in different stages of clinical development for the treatment of HER2-positive breast cancer. The purpose of this review is to provide an insight into the ADC field in cancer treatment and present a comprehensive overview of ADCs approved or under clinical investigation for the treatment of HER2-positive breast cancer.
DNA binding protein YB-1 is a part of the neutrophil extracellular trap mediation of kidney damage and cross-organ effects
Authors: Jialin Wang, Xiyang Liu, Yulu Gu, Yingying Gao, Vera Jankowski, Nina Was, Anna Leitz, Lucy K. Reiss, Yiqin Shi, Jieru Cai, Yi Fang, Nana Song, Shuan Zhao, Jürgen Floege, Tammo Ostendorf, Xiaoqiang Ding, Ute Raffetseder
Journal: Kidney International (2023)
Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy
Authors: Rasmus Erik Johansson Mortensen, Morten Orebo Holmström, Thomas Landkildehus Lisle, Jane P Hasselby, Gro L Willemoe, Özcan Met, Inge Marie Svane, Julia Johansen, Dorte L Nielsen, Inna M Chen, Mads Hald Andersen
Journal: Journal for ImmunoTherapy of Cancer (2023)

Circulating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown clinical effects in animal models of pancreatic cancer (PC). TGF-β-expressing regulatory cells are especially elevated in PC and may prevent the clinical response to immune checkpoint inhibitors (ICIs). Thus, in the present study we investigated the significance of TGF-β-specific T-cell immunity in patients with PC treated with ICI combined with radiotherapy in a randomized phase 2 study (CheckPAC).Immune responses to a TGF-β-derived epitope entitled TGF-β-15 as well as epitopes from Clostridium tetani (tetanus) and influenza were measured in peripheral blood mononuclear cells (PBMCs) with interferon-ɣ enzyme-linked immunospot assays. PBMCs were isolated before and after treatment. Correlations between immune response data and clinical data were evaluated with parametric and non-parametric statistical methods. Survival was analyzed with univariate and multivariate Cox-regression. TGF-β-15 specific T cells were isolated and expanded and examined for recognition of autologous regulatory immune cells by flow cytometry.PBMCs from 32 patients were analyzed for immune responses to the TGF-β-derived epitope entitled TGF-β-15. Patients with a strong TGF-β-specific immune response at treatment initiation had longer progression-free and overall survival, compared with patients with a weak or no TGF-β-specific immune response. This remained significant in multivariate analysis. Patients with weak and strong TGF-β-specific responses displayed similar responses towards viral antigens. Furthermore, we show that TGF-β-specific T cells from a clinical responder specifically reacted to and lysed autologous, regulatory immune cells. Finally, mimicking a TGF-β-15 vaccination, we showed that repeated stimulations with the TGF-β-15 epitope in vitro enhanced the immune response to TGF-β-15.A strong TGF-β-15 specific immune response was associated with clinical benefit and improved survival after ICI/radiotherapy for patients with PC. Importantly, the lack of TGF-β-specific T cells in some patients was not caused by a general immune dysfunction. TGF-β-specific T cells recognized regulatory immune cells and could be introduced in vitro in patients without spontaneous responses. Taken together, our data suggest that combining TGF-β-based vaccination with ICI/radiotherapy will be beneficial for patients with PC.
Integrating Psychosocial Care in the Management of Patients With Vascular Disease
Authors: Kim G. Smolderen, Zainab Samaan, Barbara Ward-Zimmerman, Lisa Fucito, Philip Goodney, Viet Le, Hussein Abu Daya, Demetria M. McNeal, Marc Bonaca, Carlos Mena-Hurtado
Journal: Journal of the American College of Cardiology (2023)
Predicting localised corrosion and mechanical performance of a PEO surface modified rare earth magnesium alloy for implant use through in-silico modelling
Authors: Kerstin van Gaalen, Conall Quinn, Marek Weiler, Felix Gremse, Felix Benn, Peter E. McHugh, Ted J. Vaughan, Alexander Kopp
Journal: Bioactive Materials (2023)

In this study, the influence of a plasma electrolytic oxidation (PEO) surface treatment on a medical-grade WE43-based magnesium alloy is examined through an experimental and computational framework that considers the effects of localised corrosion features and mechanical properties throughout the corrosion process. First, a comprehensive in-vitro immersion study was performed on WE43-based tensile specimens with and without PEO surface modification, which included fully automated spatial reconstruction of the phenomenological features of corrosion through micro-CT scanning, followed by uniaxial tensile testing. Then the experimental data of both unmodified and PEO-modified groups were used to calibrate parameters of a finite element-based surface corrosion model. In-vitro, it was found that the WE43-PEO modified group had a significantly lower corrosion rate and maintained significantly higher mechanical properties than the unmodified. While corrosion rates were ∼50% lower in the WE43-PEO modified specimens, the local geometric features of corroding surfaces remained similar to the unmodified WE43 group, however evolving after almost the double amount of time. We were also able to quantitatively demonstrate that the PEO surface treatment on magnesium continued to protect samples from corrosion throughout the entire period tested, and not just in the early stages of corrosion. Using the results from the testing framework, the model parameters of the surface-based corrosion model were identified for both groups. This enabled, for the first time, in-silico prediction of the physical features of corrosion and the mechanical performance of both unmodified and PEO modified magnesium specimens. This simulation framework can enable future in-silico design and optimisation of bioabsorbable magnesium devices for load-bearing medical applications.